International Journal of Internal Medicine 2012, 1(1): 1-5

DOI: 10.5923/j.ijim.20120101.01

Budd-Chiari Syndrome: a Clinical Approach

Silvia Hoirisch-Clapauch1,*, Olívia Barberi Luna2, Cassia Guedes Leal2,
Hanna Beatriz Thomas Sá Reilly3

1
Anticoagulation Clinic, Hospital Federal dos Servidores do Estado, Rio de Janeiro, Brazil
2
Hepatology Department, Hospital Federal dos Servidores do Estado, Rio de Janeiro, Brazil
3
Gastroenterology Department, Mayo General Hospital, County Mayo, Ireland

Abstract Budd-Chiari syndrome is characterized by supra-hepatic veins obstruction, leading to post-sinusoidal portal
hypertension that often evolves to hepatic failure. It is usually related to prothrombotic conditions, such as trombophilia,
myeloproliferative diseases or nocturnal paroxysmal hemoglobinuria. Spontaneous remissions are rare and less than a third of
the patients survive one year without treatment. We recommend that anticoagulation should be started as soon as possible
with full-dose subcutaneous heparin, postponing warfarin therapy until substantial improvement of ascites and liver con-
gestion. This approach optimizes anticoagulation, decreasing the chances of bleeding. Since January 2000, among 350 pa-
tients followed at the Anticoagulation Clinic, three fulfilled the criteria for primary Budd-Chiari syndrome and were started
on scheduled anticoagulation protocol. During three to ten years follow-up, supra-hepatic thrombosis completely resolved in
all patients and hepatic function normalized without resorting to invasive procedures or liver transplantation. Neither re-
currence of thrombotic events, nor serious bleeding events were documented. Scheduled anticoagulation is safe and improves
patient’s outcomes.
Keywords Budd-Chiari Syndrome, Thrombophilia, Anticoagulation, Heparin, Warfarin

can be increased or within normal range[5]. Early diagnosis

1. Introduction
Budd-Chiari syndrome is an uncommon disease, defined
as hepatic venous outflow obstruction, when right cardiac
failure, constrictive pericarditis or sinusoidal venooclusive
disease are excluded. Primary form usually results from
prothrombotic disorders, such as myeloproliferative disor-
ders[1], nocturnal paroxysmal hemoglobinuria[2] or throm-
bophilia[3,4], combined with a trigger that includes infection,
hormonal therapy and pregnancy[5-7]. Particularly, up to
45% of patients with primary Budd-Chiari syndrome have a
myeloproliferative disorder, about 10% have antiphosphol-
ipid antibody syndrome and no aetiology can be found in
5%[5]. Secondary form results from extrinsic hepatic venous
compression[8]. Inadequate hepatic venous outflow in-
creases sinusoidal pressure, resulting in peri-sinusoidal
hepatocyte necrosis that ultimately progresses to hepatic
failure[5].
Most Budd-Chiari patients have a dull abdominal pain on
presentation, but about 15% can be asymptomatic[5]. Ascites,
hepatomegaly, splenomegaly, and serum to ascites albumin
ratio > 1.1, indicating portal hypertension, are a rule[5,10].
Diagnostic accuracy of hepatogram is low for Budd-Chiari
syndrome: ALT, AST, γ-GT and alkaline phosphatase levels
* Corresponding author:
sclapauch@ig.com.br (Silvia Hoirisch-Clapauch)
Published online at http://journal.sapub.org/ijim
Copyright © 2012 Scientific & Academic Publishing. All Rights Reserved
is fundamental, so when Doppler-scan does not show the
suspected venous obstruction, angio-CT or angio-MRI must
be performed as soon as possible[5,10]. Liver biopsy is in-
dicated in assessing hepatocellular injury.
Although obstruction site, thrombus extent and clinical
presentation may vary significantly among patients, full-
dose anticoagulation should be promptly started, thus pre-
venting evolution to cirrhosis[5,9].
We report three patients in whom full-dose subcutaneous
heparin was given for an extended period and warfarin was
postponed until significant resolution of ascites and liver
congestion. During three to ten years of follow-up, they all
remain asymptomatic with normal hepatic function without
resorting to angioplasty, transjugular intrahepatic portosys-
temic shunt (TIPS) or liver transplantation.
2. Case Reports
● Patient 1. EAM, a 37-year-old woman, smoker since 21,
with a past history of alcohol abuse, sought for medical help
four months after having noticed abdominal and lower limbs
swelling. On admission, she had severe ascites and collateral
abdominal circulation (Figure 1). Laboratory tests revealed
sideropenic anemia, high γ-GT and alkaline phosphatase
levels, hypoalbuminemia, homozygosis for methylene tet-
rahydrofolate reductase C677T with normal homocysteine-
mia, and serum-ascites albumin gradient = 1.8. Two samples
taken more than 12 weeks apart were strongly positive for
2 Silvia Hoirisch-Clapauch et al.: Budd-Chiari Syndrome: a Clinical Approach
lupus anticoagulant and antiphospholipid antibody syndrome
was diagnosed. A Doppler-scan disclosed inferior vena cava
thrombosis and MRI showed supra hepatic venous throm-
bosis. EAM was discharged with full-dose subcutaneous
UFH twice a day and warfarin was introduced three months
later, after ascites absorption (Figure 2). She remains in
remission on oral anticoagulation five years after diagnosis.
Figure 1. Patient 1 before full-dose subcutaneous heparin
● Patient 2. GPS, heavy drinker and former smoker,
sought for medical advice at the age of 40 due to left lower
limb deep venous thrombosis and pulmonary embolism. He
was placed on warfarin for six months. During the next three
years a safenectomy was performed to treat a lower limb
deep venous thrombosis and an ileoectomy, to treat a mes-
enteric venous thrombosis. At the age of 47, he was admitted
complaining of excruciating abdominal pain. Mesenteric
venous thrombosis was diagnosed and an extended ileo-
colectomy was performed. Post surgically, a Doppler-scan
performed to elucidate persistent bloody diarrhoea showed
inferior vena cava, portal vein and supra-hepatic thrombosis.
Anticardiolipin antibody was 78 GPL (85 GPL 12 weeks
later) and antiphospholipid antibody syndrome was diag-
nosed. Seven months after full-dose subcutaneous UFH was
started, ascites subsided and warfarin replaced heparin. The
patient remains in remission ten years later.
● Patient 3. JPHO, a 2 year-old boy whose parents are first
cousins was admitted to investigate massive splenomegaly,
hepatomegaly and severe ascites that had begun four months
earlier. Screening for thrombophilia, paroxysmal nocturnal
hemoglobinuria and myeloproliferative diseases were all
negative; due to parental consanguinity, we postulate that an
uncommon mutation would be responsible for the throm-
botic tendency. Alkaline phosphatase and γ-GT levels were
high and a Doppler-scan showed supra-hepatic venous
thrombosis. Full-dose subcutaneous UFH was started and
two months later he had lost 4 kg, returning to his previous
weight, 12 kg. An ultrasound showed complete ascites
resolution and heparin was replaced by warfarin. Three years
later, he remains in partial remission, with minimal ascites.
Figure 2. Patient 1 after full-dose subcutaneous heparin
3. Thrombophilia Screening
We strongly recommend that the decision to start anti-
coagulation do not depend on a thrombophilia diagnosis.
Thrombophilia tests include a complete blood cell count, a
lipidogram, fibrinogen, antithrombin III, functional protein
C, protein S, polymorphisms for factor V Leiden,
prothrombin (factor II) G20210A, methylene tetrahydro-
folate reductase (MTHFR) C677T and A1298C, anticardi-
olipin antibodies IgG and IgM, lupus anticoagulant and β2
glycoprotein 1 IgG and IgM.
Factor V Leiden and factor II G20210A increase the
thrombotic risk in hetero or homozygosis, whereas MTHFR
increases the thrombotic risk in homozygosis or double
heterozygosis.
Antiphospholipid antibody syndrome diagnosis requires
the presence of any positive antiphospholipid antibody on
two or more occasions, at least 12 weeks apart. Antiphos-
pholipid antibodies comprise:
● Lupus anticoagulant (screening, mixing and confirma-
tion tests must be performed according to ISTH guidelines),
IgG and IgM anticardiolipin antibodies and IgG and IgM
anti-β2 glycoprotein antibodies (Elisa).
● IgG and IgM anticardiolipin antibodies are considered
positive when the value is higher than 40 GPL or MPL or >
99th percentile and high positive when the value is higher
than 80 GPL or MPL.
 International Journal of Internal Medicine 2012, 1(1): 1-5
● IgG and IgM anti-β2 glycoprotein 1 antibodies are
considered positive when the value is > 99th percentile[11].
A bone marrow aspiration and biopsy must be performed
on all patients suspected of having a myeloproliferative
disease on complete blood cell count and blood film ex-
amination. Enhanced platelet and leukocyte activation and
plasma hypercoagulability associated with Janus kinase 2
(JAK2) V617F positivity have been postulated as pathogenic
mechanisms of thrombosis in myeloproliferative disorders.
Interestingly, this mutation can be also detected in up to 44%
of all Budd-Chiari patients without overt myeloproliferative
neoplasms[1,12]. The presence of the (JAK2) mutation is
determined by polymerase chain reaction.
Factor V Leiden, factor II G20210A or MTHFR poly-
morphisms and JAK2 mutation, coded in DNA, are searched
with polymerase chain reaction for once in a lifetime and are
not influenced by the thrombotic event or anticoagulation. In
contrast, screening for hereditary anticoagulant deficiencies
or antiphospholipid antibodies presents some challenges:
● Thrombosis itself can consume antithrombin III, func-
tional protein C, protein S and antiphospholipid antibodies.
For this reason, testing should be done at least six weeks after
the thrombotic event.
● Anticoagulation may interfere with thrombophilia test-
ing: antithrombin III levels are usually reduced during
heparin treatment and low levels of protein S and functional
protein C levels can be seen during warfarin treatment.
Testing for antithrombin III, functional protein C and protein
S are usually delayed until at least one month after comple-
tion of anticoagulation, but Budd-Chiari patients are often
placed on long-term anticoagulant therapy.
● Antithrombin III and functional protein C are synthe-
sized only by hepatocytes, while protein S synthesis occurs
mainly in the liver. Chronic and acute hepatopathy may
decrease antithrombin III, protein S and functional protein C
levels.
● Protein S levels are reduced during infections, hormonal
therapy, pregnancy and puerperium, and inflammation, such
as inflammatory bowel disease.
Paroxysmal nocturnal hemoglobinuria is a rare acquired
disease characterized by a clone of blood cells lacking
GPI-anchored complement inhibitors CD55 and CD59 on
erythrocytes, which leads to intravascular hemolysis upon
complement activation and a highly increased risk of
thrombosis[13]. CD55- and CD59-deficient populations can
be demonstrated with flow cytometry.
4. Budd-Chiari Treatment
Prompt anticoagulation with full-dose subcutaneous
heparin may prevent progression to cirrhosis. Both unfrac-
tionated (UFH) and low-molecular-weight heparin (LMWH)
can be given as outpatient basis with the same efficacy,
without being monitored[14]. LMWH do not have antidote
and should be avoided whenever variceal bleeding risk is
high. Heparin doses are:
● UFH: 333 IU/kg of “dry weight” (excluding ascites and
3
edema), followed by 250 IU/kg every 12 hours.
● LMWH, such as enoxaparin: 1 mg/kg of “dry weight”
every 12 hours.
Protamine sulfate can be used for the reversal of heparin;
together they form a stable salt complex. Protamine is a weak
anticoagulant and it is important to avoid overdosing. UFH
short half-life must be taken into account when calculating
the dose of protamine sulfate[15]. To minimize side effects,
such as anaphylaxis and hypotension, protamin must be
dissolved in saline and infused slowly. Protamin doses are
based on the length of time elapsed since heparin was dis-
continued and the size of the dose:
● If the last heparin SC injection occurred less than 3
hours before, 1 mg for each 100 IU UFH.
● If the last heparin SC injection occurred 3 to less than 6
hours before, 0.75 mg for each 100 IU UFH.
● If the last heparin SC injection occurred 6 to less than 9
hours before, 0.5 mg for each 100 IU UFH.
● If the last heparin SC injection occurred less than 3
hours before, 0.25 mg for each 100 IU UFH.
Although protamine sulfate can fully reverse the effect of
UFH, it only partly neutralizes the effect of LMWH. Re-
combinant activated factor VII (rFVIIa) is a good alternative
for reversal of LMWH anticoagulation; unfortunately,
rFVIIa may increase the risk of thromboembolic events[16].
Because many patients present with prolonged PT-INR
and thrombocytopenia, physicians are cautious to prescribe
drugs that could increase the risk of variceal bleeding[5].
However, it must be considered that:
● Patients with primary Budd-Chiari have a thrombotic
tendency. Synthesis of most coagulation factors occur in the
hepatocyte. Also, synthesis of natural anticoagulants and
components of the fibrinolytic pathway occurs mainly in the
liver.
● Neither low-platelet count nor prolonged PT-INR pre-
vents thrombotic events.
Also, when prolonged PT-INR is due to liver injury, vi-
tamin K seldom corrects the problem.
Warfarin therapy should be postponed until significant
resolution of ascites and liver congestion, which normally
occurs many weeks after hospital discharge. This approach
avoids frequent warfarin adjustments related to progressive
liver congestion remission and diuretics tapping. In addition,
when invasive procedures such as biopsies or paracentesis
are required, heparins but not warfarin can be discontinued
for few hours.
Treatment with warfarin must be monitored by someone
with extensive experience in handling of this medication,
because food, caffeine-containing beverages and many other
medications, particularly β-blockers, spironolactone, and
omeprazole, may impair or potentiate the anticoagulant
effect of warfarin[17-23].
It must be remembered that long-term anticoagulation is
associated with an increased risk of osteoporosis and frac-
tures[24, 25]. To prevent bone loss, patients on oral antico-
agulants or heparins must be advised to engage in low- im-
pact exercise on a daily basis.
4 Silvia Hoirisch-Clapauch et al.: Budd-Chiari Syndrome: a Clinical Approach
Estrogens, tamoxifen, third-generation progestins and
antiangiogenic drugs, such as thalidomide or lenalidomide,
increase the risk of venous thromboembolic events and must
be avoided[6,12,26]. Variceal bleeding prophylaxis is indi-
cated for portal hypertension and diuretics or paracentesis for
ascites relief[5]. It is important to consider that dehydration
increases the risk of thrombosis.
Polimorphisms as homozygous methylene tetrahydro-
folate reductase C677T or A1298C, or double heterozygous
C677T/A1298C increase the risk for hyperhomocysteinemia
in patients deficient in folic acid, pyridoxine (vitamin B6) or
cobalamin (vitamin B12). Hyperhomocysteinemia is a
modifiable risk factor for thrombotic diseases. Daily sup-
plementation with folic acid 5-10 mg usually prevents hy-
perhomocysteinemia or normalizes homocysteine plasmatic
levels. Some patients may require additional vitamin B6 and
vitamin B12 supplementation.
Some issues must be addressed regarding paroxysmal
nocturnal hemoglobinuria patients. It has been shown that
anticoagulation reduces the risk but does not completely
prevent thrombosis.Eculizumab, a monoclonal antibody
against complement factor C5, has clearly improved the
prognosis of the disease, effectively reducing intravascular
hemolysis and thrombotic risk[13].
Angioplasty is frequently recommended for symptomatic
patients with short stenosis[5,10]. However, invasive pro-
cedures and mechanical devices could trigger additional
thrombotic events or enhance extension of preexisting ones
and should be performed with caution. Furthermore, recur-
rence after liver transplantation is about 27% and, as might
be expected, antithrombotic prophylaxis with aspirin and
hydroxiurea for myeloproliferative syndromes or antico-
agulation for patients with thrombophilia after the procedure
has dramatically improved the results[27,28].
5. Conclusions
Major goal in Budd-Chiari syndrome is to restore vessel
patency, preventing evolution to hepatic failure. Because
hepatic congestion and frequent adjustments of other drugs
can interfere with warfarin, patients with portal hypertension
are difficult to manage with oral anticoagulants. We suggest
that Budd-Chiari patients be treated initially with full-dose
subcutaneous heparin, postponing warfarin therapy until
substantial resolution of ascites and liver congestion.
Scheduled anticoagulation reduces the risk of bleeding and
increases the chances for long-term remission without re-
sorting to angioplasty, TIPS or liver transplantation.
ACKNOWLEDGEMENTS
The authors would like to thank Dr. Flavio D. Manela and
Mr. William Reilly who assisted with the preparation and
proof-reading of the manuscript.
REFERENCES
[1] Raj K. Patel, Nicholas C. Lea, Michael A. Heneghan, Nigel B.
Westwood, Dragana Milojkovic, Murugaiyan Thanigaikumar,
Deborah Yallop, Roopen Arya, Antonio Pagliuca, Joop
Gäken, Julia Wendon, Nigel D. Heaton, Ghulm J. Muft,
Prevalence of the activating JAK2 tyrosine kinase mutation
V617F in the Budd-Chiari syndrome, Gastroenterology
130:2031-2038, 2006.
[2] Jildou Hoekstra, Frank W. Leebeek, Aurelie Plessier, Sebas-
tien Raffa, Sarwa Darwish Murad, Jorg Heller, Antoine Ha-
dengue, Carine Chagneau, Elwyn Elias, Massimo Primignani,
Juan-Carlos Garcia-Pagan, Dominique C. Valla, Harry L.A.
Janssen, Paroxysmal nocturnal hemoglobinuria in Budd
Chiari syndrome: findings from a cohort study, Journal of
Hepatology 51:696-706, 2009.
[3] Mordechai Averbuch and Yoram Levo, Budd-Chiari syn-
drome as the major thrombotic complication of systemic lu-
pus erythematosus with the lupus anticoagulant, Annals of the
Rheumatic Diseases 45:435-437, 1986.
[4] Ron Hoffman, Assy Nimer, Naomi Lanir, Benjamin Brenner,
Yaacov Baruch, Budd-Chiari syndrome associated with fac-
tor V Leiden mutation: a report of 6 patients, Liver Trans-
plantation and Surgery 5:96-100, 1999.
[5] Dominique-Charles Valla, Primary Budd-Chiari syndrome,
Journal of Hepatology 50:195-203, 2009.
[6] Dominique Valla, Monique G. Le, Thierry Poynard, Nathalie
Zucman, Bernard Rueff, Jean-Pierre Benhamou, Risk of he-
patic vein thrombosis in relation to recent use of oral con-
traceptives, Gastroenterology 90:807-811, 1986.
[7] Mehnaaz Sultan Khuroo and Dharamveer Datta, Budd-Chiari
syndrome following pregnancy. Report of 16 cases with
roentgenologic, hemodynamic and histologic studies of the
hepatic outflow trait, American Journal of Medicine
68:113-121, 1980.
[8] Jurgen Ludwig, Etsuko Hashimoto, Douglas McGill, Jona-
than Van Heerden, Classification of hepatic venous outflow
obstruction: ambiguous terminology of the Budd-Chiari
syndrome, Mayo Clinic Proceedings 65:51-55, 1990.
[9] Vladimir Bogin, Amadeo Marcos, Thomas Shaw-Stiffel,
Budd-Chiari syndrome: in evolution, European Journal of
Gastroenterology and Hepatology 17:33-35, 2005.
[10] John D. Horton, Francisco L. San Miguel, Jorge A. Ortiz,
Budd Chiari syndrome: illustrated review of current man-
agement, Liver International 28:455-466, 2008.
[11] Katrien Devreese and Marc F. Hoylaert, Laboratory diagnosis
of the antiphospholipid syndrome: a plethora of obstacles to
overcome, European Journal of Haematology 83:1-16, 2009.
[12] Ida Martinelli and Valerio De Stefano, Rare thromboses of
cerebral, splanchnic and upper-extremity veins. A narrative
review, Thrombosis and Haemostasis 103:1136-1144, 2010.
[13] Sandra T. A. van Bijnen, Waander L. van Heerde, Petra Muus,
Mechanisms and clinical implications of thrombosis in pa-
roxysmal nocturnal hemoglobinuria, Journal of Thrombosis
and Haemostasis 10:1-10, 2012.
[14] Clive Kearon, Jeffrey S. Ginsberg, Jim A. Julian, James
Douketis, Susan Solymoss, Paul Ockelford, Sharon Jackson,
Alexander A. Turpie, Betsy MacKinnon, Jack Hirsh, Michael
 International Journal of Internal Medicine 2012, 1(1): 1-5
Gent; for the Fixed-Dose Heparin (FIDO) Investigators,
Comparison of fixed-dose weight-adjusted unfractionated
heparin and low-molecular-weight heparin for acute treat-
ment of venous thromboembolism, Journal of the American
Medical Association 296:935-942, 2006.
[15] Sam Schulman, Nick R. Bijsterveld, Anticoagulants and their
reversal, Transfusion Medicine Reviews 21:37-48, 2007.
[16] Jorgen Ingerslev, Tomas Vanek, Srdjana Culic. Use of re-
combinant factor VIIa for emergency reversal of anticoagu-
lation, Journal of Postgraduate Medicine 53:17-22, 2007.
[17] Jack Hirsh, Valentin Fuster, Jack Ansell, Jonathan Halperin,
American Heart Association/American College of Cardiol-
ogy Foundation guide to warfarin therapy, Journal of the
American College of Cardiology 41:1633-1652, 2003.
[18] Caroline Bolton‐Smith, Rosemary J. G. Price, Steven T.
Fenton, Dominic J. Harrington, Martin J. Shearer, Compila-
tion of a provisional UK database for the phylloquinone (vi-
tamin K) content of foods, British Journal of Nutrition
83:389-399, 2000.
[19] John L. Weihrauch and Ashok S. Chatra, Provisional table on
the vitamin K content of foods. US Department of Agriculture
National Nutrient Database for Standard Reference. Release
18. Online available at: http://www.nal.usda.gov/fnic/foodco
mp/Data/SR18/nutrlist/sr18a430.pdf
[20] Deborah J. Shaw, Christine Leon, Stoyko Kolev, Virginia
Murray. Traditional remedies and food supplements: a five
year toxicological study (1991-1995). Drug Safety 17:342-
356, 1997.
[21] Adriane Fugh-Bergman, Herb-drug interactions, Lancet
355:134-138, 2000.
[22] Elaine M. Hylek, Heather Heiman, Steven J. Skates, Mary A.
5
Sheehan, Daniel E. Singer. Acetaminophen and other risk
factors for excessive warfarin anticoagulation, Journal of the
American Medical Association 279:657-662, 1998.
[23] Silvia Hoirisch-Clapauch and Paulo Roberto Benchi-
mol-Barbosa, Warfarin resistance and caffeine containing
beverages, International Journal of Cardiology 156:e4-e5,
2012.
[24] Pedro J. Caraballo, John A. Heit, Elizabeth J. Atkinson, Marc
D. Silverstein, W. Michael O'Fallon, M. Regina Castro, L.
Joseph Melton III, Long-term use of oral anticoagulants and
the risk of fracture, Archives of Internal Medi-
cine 159:1750-1756, 1999.
[25] Raghav Rajgopal, MacKenzie Bear, Martin K. Butcher,
Stephen G. Shaughnessy, The effects of heparin and low
molecular weight heparins on bone, Thrombosis Research
122:293-298, 2008.
[26] Thomas G. DeLoughery, Venous thrombotic emergencies,
Hematology Oncology Clinics of North America 24:487-500,
2010.
[27] Gilles Mentha, Emiliano Giostra, Pietro E. Majno, Wolf O.
Bechstein, Peter Neuhaus, John O’Grady, Raaj K. Praseedom,
Andrew K. Burroughs, Yves P. Le Treut, Preben Kirkegaard,
Xavier Rogiers, Bo-Goran Ericzon, Krister Hockerstedt,
Rene Adam, Juergen Klempnauer, Liver transplantation for
Budd-Chiari syndrome: A European study on 248 patients
from 51 centres, Journal of Hepatology 44:520-528, 2006.
[28] Srinath Chinnakotla, Goran B. Klintmalm, Peter Kim, Koji
Tomiyama, Erik Klintmalm, Gary L. Davis, James F. Trotter,
Rana Saad, Carmen Landaverde, Marlon F. Levy, Robert M.
Goldstein, Marvin J. Stone, Long-term follow-up of liver
transplantation for Budd-Chiari syndrome with antithrom-
botic therapy based on the etiology, Transplantation
92:341-345, 2011.